During development mammalian neurons grow, the local environment is permissive for such growth, and guidance cues are present that direct neurons to their specific targets, collectively leading to formation of functional neural circuits.In mature differentiated neurons the molecular machinery necessary for intrinsic growth is absent. However, injury to axons in the peripheral nervous system (PNS) increases intrinsic growth in sensory and motor neurons, and in optimal conditions, regeneration occurs, with restoration of function. The objective of this proposal is to study changes in the rate and extent of regeneration in the PNS with aging in mice, a subject that has received little attention, particularly at a mechanistic level, even though peripheral neuropathies and nerve lesions are common in the elderly. This proposal is based on our preliminary data showing that aging in mice slows regeneration, and that this is not associated with a change in intrinsic neuronal growth but that Schwann cells in old animals have a differential transcriptional alteration after nerve injury to young mice. The aim now will be to mechanistically interrogate aged Schwann cell function and determine what age- dependent pathways affect peripheral nerve regeneration. These data will provide a basis for future attempts to see if regenerative capacity can be restored in aged mice to levels seen in young mice, as a first step towards the development of potential therapeutic interventions in patients. PUBLIC HEALTH RELEVANCE: Axons of the PNS, unlike those of the CNS, can regenerate after injury. Although it has been appreciated for some time that the ability of axons of the PNS to regenerate decreases as a function of age, the mechanisms responsible for this have yet to be elucidated, so my goal for this project is to determine whether aging produces dysfunction within the Schwann cell compartment, which leads to decreased functional recovery after nerve injury in old animals. My goal is to determine what specific Schwann cell pathways are altered with age, and how these affect peripheral regeneration.